Introduction: Nausea and vomiting are the most common and distressing side effects of chemotherapy because they negatively impact on quality of life and treatment compliance. Adequate control of nausea and vomiting in children receiving chemotherapy is imperative. Currently, the first-line drug for the prophylaxis and treatment of chemotherapy-induced nausea and vomiting (CINV) in paediatric patients is the serotonin (5HT3) receptor antagonist, ondansetron, administered intravenously. However, the parenteral route of administration of this drug is now being questioned as it is inconvenient for children and there is pressure to switch to an available oral formulation. The aim of this study was to evaluate the ease of administration, efficacy and cost-effectiveness of intravenous (IV) and oral tablet (OT) formulations of ondansetron in paediatric cancer patients receiving moderately emetogenic chemotherapy at the Steve Biko Academic Hospital in Pretoria, Gauteng (South Africa).Methods: It was an open-label, parallel, randomized trial. Thirty (30) patients scheduled to receive moderately emetogenic chemotherapy were recruited from the paediatric oncology department of the hospital. These patients were randomized to receive the same dose of either IV or OT ondansetron for the prophylaxis of CINV for one chemotherapy cycle. The efficacy of the agents was determined using a visual analogue scale (VAS) completed by the paediatric patients, which was compared to a one page questionnaire completed by the parents of the patients. Both questionnaires were completed at the end of chemotherapy (treatment period) as well as after a week without chemotherapy treatment (follow-up period). The patients’ plasma concentrations of ondansetron at four different time points were quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS). The ondansetron plasma concentrations obtained in the IV group were compared to those obtained in the OT group. The cost-effectiveness calculations included the direct costs of antiemetic prophylaxis and treatment, the use of any rescue medication and the length of hospital stay. Results: The VAS revealed that patients who were given antiemetic prophylaxis with OT ondansetron experienced less acute and delayed nausea than the patients in the IV ondansetron group; however, these differences were not statistically significant (p=0.538). Vomiting was similar in the two groups (p=1). There was a statistically significant difference between the patients and their parents in the perception of acute nausea (p=0.018), with parents overstating the level of acute nausea felt by their children. The plasma concentrations of ondansetron in patients on the IV formulation were higher than the ones in patients on the OT formulation at all the time points investigated. At 30 minutes post-dosing the mean plasma concentration of ondansetron in the IV group was significantly higher than in the OT group (p=0.0015), but the differences in plasma concentrations between the two groups from 2 hours were fairly comparable. The cost of antiemetic prophylaxis for IV ondansetron was significantly higher than the cost of antiemetic prophylaxis using the equivalent OT dose (p=0.0351). Conclusion: For the prevention of CINV, OT ondansetron, a 5HT3 receptor antagonist, proved to be an easy to use and cost-effective alternative to IV ondansetron in paediatric cancer patients receiving moderately emetogenic chemotherapy treatment.